Ventral Hippocampal Infusions of C20:0 Ceramide Stimulate Microglia and Induce Anhedonia-like Behavior in Female and Male Rats

ABSTRACT Increased long-chain C20:0 ceramides have been found in the serum of patients with depression. Moreover, ceramides are linked with increased microglia reactivity and inflammatory cytokine production, which are associated with depression. Since ceramides can readily cross the blood brain barrier, peripheral C20:0 ceramides could enter the brain, activate microglia, and induce depressive-like behavior. In this study, we determined whether localized infusion of C20:0 ceramides into the ventral hippocampus (VH) of rats is sufficient to activate microglia and induce depressive-like behaviors. Adult male and female rats received infusions of C20:0 ceramides or vehicle solution every other day for 2 weeks. After the third infusion, C20:0-infused animals showed reduced sucrose preference suggesting anhedonia-like behavior. However, 4-6 days after the last infusion, animals infused with C20:0 ceramides did not show anhedonia-like or despair-like behavior suggesting the behavioral effect was reversible. After the final behavioral test, C20:0-infused animals had more Iba-1+ microglia in the VH. Despite the increased number of VH microglia, the expression of inflammatory genes was not increased. In conclusion, our data suggest that localized increases in C20:0 ceramides in the VH are sufficient to induce microglia activation and reversible anhedonia-like behavior.